In recent years, coronary cardio-circulary diseases, e.g., atherosclerosis and hypercholesterolemia, have increasingly become a major cause of deaths. It has been reported that an elevated plasma cholesterol level causes the deposition of fat, macrophages and foam cells on the wall of blood vessels, such deposit leading to plaque formation and then to atherosclerosis(Ross, R., Nature, 362, 801-809(1993)).
Specifically, it has been reported that a high ratio of plasma low density lipoproteins(LDL) to total cholesterol causes atherosclerosis very easily, while plasma HDL-cholesterol is beneficial to health. A recent study exhibited that increase in the plasma HDL level is inversely related to the occurrence of a heart disease(Barter P. J., Rye K. A., High density lipoproteins and coronary heart disease, Atherosclerosis 121:1-12(1996)).
Lamarche et al. have found that a combination of hypertriglyceridemia, a low plasma HDL level, an abdominal fatness and the like is a major risk factor causing atherosclerosis, thereby discovering that a low plasma HDL level is also an important risk factor of atherosclerosis (Lamarche B., Lewis G. F., Atherosclerosis prevention for the next decade: risk assessment beyond low density lipoprotein cholesterol, Can. J. Cardiol. 14:841-851(1998)). In addition, Lacko et al. have verified that plasma HDL has anti-inflammatory and anti-atherosclerosis activities(Lacko A. G., Miller N. E., International symposium on the role of HDL in disease prevention: report on a meeting, J. Lipid Research 38:1267-1273(1997)).
Therefore, numerous efforts have been made to develop medicines to increase the plasma HDL level; and, as a result, a pharmaceutical composition for increasing the plasma HDL level has been reported(U.S. Pat. No. 5,783,600, issued on Jul. 21, 1998). However, said composition comprises chemically synthesized compounds as an active ingredient, which may induce adverse side effects in a human body in terms of toxicity or pharmaceutical activities.
The present inventors have endeavored to develop a non-toxic plasma HDL level increasing agent from natural materials, and, as a result, have discovered that bioflavonoids isolated from edible plants are effective to increase the plasma HDL level.
Generally, various bioflavonoids, such as those listed in Table I, are present in the citrus peel(Horowitz, R. M. et al., J. Org. Chem., 25, 2183-2187(1960)). Hesperidin is the major bioflavonoid component found in orange, lemon and tangerine; naringin represents the major bioflavonoid component in grapefruit; and naringin and hesperidin are present in citron in nearly equal amounts.
TABLE I ______________________________________ Citrus fruit Bioflavonoids ______________________________________ Grapefruit apigenin, dihydrokaempferol, eriodictyol, hesperetin, hesperidin, isorhamnetin, isosakuranetin, neohesperidin, poncirin, quercetin, rutin Lemon apigenin, apigenin 7-rutinoside, chrysoeriol, diosmin, eriocitrin, hesperidin, isorhamnetin, limocitrin limocitrol, luteolin 7-rutinoside, naringin, neohesperidin, poncirin, quercetin Orange auranetin, hesperidin, isosakuranetin 7- rutinoside, naringin, neohesperidin, nobiletin, rutin, sinensetin, tangeretin, vitexin Tangerine hesperidin, nobiletin, tangeretin ______________________________________
It has been reported that the bioflavonoids isolated from citrus peel have an anti-oxidative, anti-cancer, anti-viral and blood-pressure lowering activities(Saija, A., et al., Free Radical Biol. Med., 19, 481-486(1995); Matsubara, Y., et al., Japan Organic Synthesis Chem. Association Journal, 52, 318-327(1994, Mar.); Galati, E. M., et al., Farmaco., 51(3), 219-221(1996, Mar.); Felicia, V., et al., Nutr. Cancer, 26, 167-181(1996); EP 0352147 A2(1990. 1. 24); and Kaul, T. N., et al., J. Med. Viol., 15, 71-75(1985)).
However, bioflavonoids have never been reported to have plasma HDL level increasing activity.